Management of Retinitis Pigmentosa

ELIOT L. BERSON, MD

Retinitis pigmentosa (RP) has a prevalence of about 1 in 4000; an estimated 2 million people are affected worldwide. The condition is most often inherited by an autosomal dominant, autosomal recessive, or X-linked mode of transmission. Affected patients usually report night deficiency and difficulty with adaptation in adolescence, loss of midperipheral and then far peripheral visual field in young adulthood, development of tunnel vision in middle life, and eventual loss of central vision after age 60. Clinical findings in the typical forms of retinitis pigmentosa include elevated final dark adaptation thresholds, attenuated retinal vessels, intraretinal bone spicule pigmentation around the midperiphery in most cases, and reduced and delayed full-field electroretinograms (ERGs). The ERGs show more loss of rod function than cone function or comparable loss of rod and cone function. The majority develop central posterior subcapsular cataracts and some have cystoid macular edema (CME). Many develop waxy pallor of the optic discs in the advanced stage. About 20% of cases have associated hearing loss designated as Usher syndrome. Histologic studies of autopsy eyes have shown that loss of vision is due to degeneration of rod and cone photoreceptors across the retina.¹

Mutations in over 45 causative genes account for 50% to 60% of cases; the most common genes involved are the rhodopsin gene, the Usher IIA gene, and the RPGR gene.² These genes may be subclassified based on the known or presumed function of encoded proteins. These genes may affect the phototransduction cascade, vitamin A metabolism, photoreceptor structure, photoreceptor signaling or cell-cell interactions, RNA intron splicing factors, intracellular transport of proteins, maintenance of cilia or ciliated cells with a possible role in intracellular trafficking, phagocytosis, and other yet to be defined functions of the photoreceptors and pigment epithelium.² A current list of genes causing retinitis pigmentosa is maintained online by RetNet at www.sph.uth.tmc.edu/retnet.

TREATMENT OF TYPICAL FORMS OF RETINITIS PIGMENTOSA WITH VITAMIN A

While monitoring the natural course of RP, a risk factor analysis revealed that patients self-treating with a separate capsule of vitamin A showed less progression by ERG testing than those taking only a multivitamin or no vitamin supplements. Many of the patients who were taking vitamin A were also taking a separate vitamin E capsule, so it was not clear whether vitamin A, vitamin E, or the combination was therapeutic. This provided the rationale for a randomized, controlled, phase 3 clinical trial for adult patients (age 18 to 49 years) with typical RP, including those with partial hearing loss (Usher syndrome, type 2).

This trial showed that vitamin A palmitate 15,000 IU/day, on average, slowed the rate of progression of disease as monitored by the 30-Hz flicker cone ERG, while vitamin E 400 IU/day appeared to hasten the course of disease. The beneficial effect of vitamin A was statistically significant at the P=.01 level for all randomized patients (n=601) and at the P<0.001 level for a subset of patients (n=354), designated as the higher amplitude cohort, with slightly higher initial full-field cone ERG amplitudes (≥0.68 μV at baseline) who could be followed more precisely over 4 to 6 years (Table 1). The adverse effect of vitamin E was statistically significant at the P=0.04 level for the higher amplitude cohort but was not significant for all randomized patients.³ The beneficial effect of vitamin A was also observed in preserving visual field area among a subset (n=125) who could perform visual fields with ≤ 5% intervisit variability.⁴ These findings have led to the recommendation that most adults with the typical forms of RP should take vitamin A palmitate 15,000 IU/day and avoid high-dose vitamin E supplements.^3,4 Vitamin A appears to rescue remaining cones, thereby, helping to explain how one supplement can help patients with many different rod-specific gene defects. Vitamin E appears to inhibit the absorption or transport of vitamin A, providing a possible explanation for its adverse effect.³

Patients who take vitamin A palmitate 15,000 IU/day should have a fasting serum vitamin A and liver function profile prior to treatment and annually thereafter. Women who are pregnant or planning to become pregnant should not take vitamin A palmitate at this dose because of the increased risk of birth defects. Postmenopausal women and men over age 49 on this treatment should monitor their bone health because of the slight (0.5% to 1%) increased risk of hip fractures among patients who take vitamin A over the long term.^5,6 Patients who have had a renal transplant should not take this dose of vitamin A as they have excessive renal reabsorption of vitamin A and are more susceptible to toxicity. Patients on chronic doxycycline should not take vitamin A because the combination has been associated with increased intracranial pressure. In adults with retinitis pigmentosa, doses of vitamin A palmitate less than 15,000 IU/day have not been found to be therapeutic and doses greater than 25,000 IU/day are potentially toxic over the long term. Beta-carotene, the precursor of vitamin A, is not a suitable substitute for vitamin A palmitate in the context of this treatment, as it is not predictably converted into vitamin A. No significant toxic effects have been observed in adults with retinitis pigmentosa on 15,000 IU/day.⁷

Children with retinitis pigmentosa were not included in this trial; therefore, no formal recommendation can be made for patients under age 18. However, with the agreement of the parents and pediatrician, if liver function is normal and children are above the lower fifth percentile of weight for their height and gender, a trial of vitamin A palmitate 5,000 IU/day can be considered for those age 6 to 10 years; 10,000 IU/day for those age 10 to 15 years, and 15,000 IU/day for those age 15 and older. A list of sources of vitamin A palmitate is maintained by the Foundation Fighting Blindness (www.fightblindness.org).

ADDITIONAL TREATMENT OF TYPICAL RP WITH AN OMEGA-3–RICH OILY FISH DIET

During the vitamin A and E trial, a subset of patients with higher red blood cell (RBC) docosahexaenoic acid (DHA) levels were found to have a significantly slower rate of progression of retinitis pigmentosa than a subset with lower RBC DHA levels. This prompted a second randomized controlled phase 3 trial for 221 patients (age 18 to 55 years) with typical retinitis pigmentosa who were assigned to either 1200 mg/day of DHA or to a group given control fatty acid capsules. All participants received vitamin A palmitate 15,000 IU/day. This trial showed that DHA supplementation 1200 mg/day did not, on average, slow the course of this condition over 4 years, as monitored primarily by the Humphrey Field Analyzer (Carl Zeiss Meditec, Dublin, CA). This precludes any general recommendation of DHA supplementation for this condition.⁸

However, a subgroup analysis among those on vitamin A prior to entry in this trial and during the trial as well, but not DHA supplementation, revealed that those eating ≥0.2 g/day of omega-3–rich oily fish (ie, equivalent to one or two 3-oz servings of oily fish per week) showed significantly (P=0.02) less loss of central visual field sensitivity as monitored with the Humphrey Field Analyzer (total point score with a size V white target) than those eating <0.2 g/day (Table 2). This observation has led to the recommendation that adults already taking vitamin A palmitate should also eat one or two 3-oz servings per week of omega-3–rich fish (ie, salmon, tuna, mackerel, herring, or sardines), of which DHA is a major constituent.⁹

Three to 4 months after starting the omega-3–rich fish diet (to allow sufficient time for red blood cell turnover), patients should have a fasting RBC DHA as a measure of intraretinal DHA to see if the level is at least 4% of total RBC fatty acids, as this level has been associated with significant slowing of the condition as monitored by visual field sensitivity.⁹ RBC DHA levels are measured in only a few laboratories, a list of which is maintained on the Foundation Fighting Blindness Web site. If the level is less than 4%, then the patient is not eating sufficient oily fish and should increase their intake by an additional serving per week; their RBC DHA should be rechecked in 3 to 4 months. Once the RBC DHA is at the level of 4% to 7% of total RBC fatty acids, it should be monitored annually along with fasting serum vitamin A and liver function. It has been estimated that the combination of vitamin A with an oily fish diet would, on average, provide a 60% to 70% slowing per year that would result in a total of almost 20 years of visual preservation for patients who start this regimen in their mid 30s; this should make it possible for many RP patients to retain useful vision for their entire lives.⁹

This second trial also showed that adults starting vitamin A palmitate 15,000 IU/day for the first time should also be treated with DHA supplementation 1200 mg/day for 2 years to shorten the interval for vitamin A to achieve its benefit. After 2 years, patients should continue the vitamin A palmitate, stop DHA capsules (because of a possible adverse effect of vitamin A plus high-dose DHA over the long term), and then eat one or two 3-oz servings per week of omega-3–rich fish. Some 3 to 4 months after stopping the DHA capsules, these patients should check their fasting RBC DHA level as described above.⁹ Sources of DHA capsules are also provided on the Foundation Fighting Blindness Web site.

It is remarkable that treatment with a single vitamin, namely vitamin A, has been shown to be beneficial on average for patients with typical retinitis pigmentosa, even though they are losing vision due to many different gene defects. By way of background, rods apparently can live without cones (eg, achromatopsia), but cones cannot live without rods (eg, retinitis pigmentosa). Under conditions of daylight, both cones and rods are activated by light in normal individuals; the cone signal arrives first at the ganglion cells, which become refractory to rod input, and therefore normal subjects see in color under daylight conditions. The rod response is not wasted as the light-activated rods expel the used form of vitamin A (i.e., all-trans-retinol) that can be isomerized by nearby Müller cells to 11-cis-retinol. The 11-cis-retinol is then transported to cones, which convert the vitamin A into the form used for visual excitation (ie, 11-cis-retinal). Therefore, under daylight conditions, it has been proposed that normally rods are giving cones vitamin A via Müller cells.^10,11 Interphotoreceptor retinoid binding protein (IRBP) transports vitamin A between these cells and from the retinal pigment epithelium (RPE) to the photoreceptors as well. Release of vitamin A from IRBP requires DHA which is present in high concentration in an oily fish diet. Stated in another way, DHA facilitates the delivery of vitamin A from IRBP to cones.¹² Despite many different gene defects, the patients with typical retinitis pigmentosa are losing rods among remaining cones, thereby resulting in a vitamin A-deficient and DHA deficient milieu in the retina.

With this proposed model in mind, patients are advised that, since they are night blind due to loss of rods and are, therefore, vitamin A and DHA deficient in the retina, they require vitamin A supplementation to replace their rods, and they require DHA-rich fish to enhance delivery of vitamin A to their remaining cones. Too much DHA in the retina (i.e., RBC DHA >7%) appears to have an adverse effect on retinal function over the long term,⁹ possibly due to excessive delivery of vitamin A to the photoreceptors from IRBP. Therefore, patients with typical RP should not take 1200 mg of DHA by capsules for more than 2 years or eat too much oily fish while taking vitamin A palmitate. If patients cannot eat oily fish, they are advised to take 200 mg/day of DHA by capsule as a substitute, but they are reminded that the efficacy data are based on combining vitamin A palmitate with naturally oily fish.

TREATMENT OF RARE FORMS OF RP

Three rare forms of retinitis pigmentosa have also yielded to treatment. Specifically, patients with retinitis pigmentosa and hereditary abetalipoproteinemia (Bassen-Kornzweig disease) should be treated with a low-fat diet and vitamins A, E, and K.^13-15 Patients with Refsum disease should be treated with a low-phytol, low–phytanic acid diet (i.e., excluding dark green, leafy vegetables, animal fats, and milk products) while maintaining body weight.^16,17 Patients with familial isolated vitamin E deficiency should be treated with oral vitamin E supplementation.^18,19 In the case of Bassen-Kornzweig disease, the disease should be suspected if the patient has fat malabsorption, acanthocytosis, and low serum vitamin A and vitamin E levels; the abnormal ERGs in this condition can be reversed to normal with vitamin A in the early stages. In the case of Refsum disease, the condition should be suspected if the patient has loss of smell, unusually dry skin, electrocardiogram abnormalities, and a peripheral neuropathy. Patients with familial isolated vitamin E deficiency usually present in adulthood with not only retinitis pigmentosa but also ataxia, dysarthria, and low serum vitamin E levels.

OTHER ASPECTS OF MANAGEMENT

Patients with retinitis pigmentosa are advised to wear dark sunglasses with tinted side shields outdoors during the day. Because light dissociates vitamin A from opsin, sunglasses can be thought of as a way of keeping vitamin A in the photoreceptors, although there is no proof that light deprivation will slow the human disease. The sunglasses should be as dark as can be tolerated without compromising vision. As retinitis pigmentosa becomes more advanced, the remaining nasal peripheral field in 1 eye may compensate in part for the loss of midperipheral temporal field in the fellow eye so that patients have better mobility with both eyes than with 1 eye. Since the patient requires both eyes for mobility, cataract surgery on a given eye should be done only if absolutely necessary.

As a general guideline, cataract surgery should be deferred as long as the patient can read with either eye.²⁰ Cataract surgery in young adults is sometimes not well received because the patient cannot coordinate the operated eye that no longer has accommodation with the unoperated eye. Cataract surgery in both eyes also is sometimes unwelcome among patients with advanced retinitis pigmentosa because these patients cannot use a bifocal, as use of a bifocal can further compromise their remaining constricted visual fields. For those patients with impaired night vision with better than 20/200 vision and a central field diameter greater than 20° in at least one eye, a monocular ITT Night Vision (Roanoke, VA) Pocket Scope (www.nightvision.com) could be considered that would help patients use their remaining cones to achieve their best daylight vision at night.²¹

Patients with reduced central vision can benefit from a closed-circuit television for reading, if they still have sufficient central field. Patients with profoundly constricted fields should be advised to have mobility training. For those who have CME by ophthalmoscopy or optical coherence tomography (OCT), a trial of ketorolac tromethamine (Acular, Allergan), prednisolone acetate (Pred Forte, Allergan), or dorzolamide hydrochloride (Trusopt, Merck) drops bid for 6 weeks should be considered to see if visual acuity improves and macular edema resolves by OCT. If these drops are unsuccessful, a trial of oral acetazolamide 250 mg bid for the same period could be attempted. If the macular edema is severe and unresponsive to drops or acetazolamide, local injections of steroids could be considered.^22-24 Some patients with CME do not respond to any of these treatments and some have had spontaneous improvement.

The progression of retinitis pigmentosa can be monitored through almost its entire course by narrow bandpassed filtered, computer averaged cone ERGs. Patients can have nondetectable full-field cone ERGs by conventional recording without computer averaging (i.e., <10 μV, lower normal = 50 μV) and still retain considerable vision for long periods of time before they reach virtual blindness (i.e., loss of the ability to walk out of a well-lighted room without assistance). Virtual blindness usually occurs when the cone responses fall to about 0.05 μV. A cone ERG actuarial table (Table 3) has been developed for patients with typical RP that allows estimates of the long-term visual prognoses of patients with this condition (i.e., time to reach 0.05μV).

Table 3 is based on data from 6553 visits among 1039 patients age 2 to 71 years followed for 3 to 29 years. If patients wish to know their long-term visual prognosis, they should have narrow bandpassed filtered, computer averaged cone ERG testing, preferably at 2-year intervals for 3 to 4 times to determine to what extent their rate of decline corresponds to the average rate. About 25% of patients with nondetectable conventional ERGs have sufficient cone ERG function with narrow bandpassed filtered, computer averaged recordings to suggest that they will retain some useful vision to age 80 or beyond without treatment. Knowledge of the remaining cone ERG amplitude often reduces patient anxiety and helps patients plan for their future.²⁵

Vitamin A is not recommended for atypical forms of retinitis pigmentosa including pericentral retinitis pigmentosa²⁶ and paravenous retinitis pigmentosa,²⁷ as patients with these conditions were not included in the vitamin A and vitamin E trial and there is no evidence that vitamin A will benefit such patients. Patients with another atypical form of retinitis pigmentosa, termed cone-rod degeneration²⁸ (i.e., predominant loss of cone function with considerable remaining rod function with a cone ERG to rod ERG amplitude ratio of 1:20 or less), also were not included in these trials, and, therefore, vitamin A is not recommended for these patients. Cone-rod degeneration should be suspected if the patient initially presents with some reduction of visual acuity and signs of macular degeneration that seem to spread peripherally with later development of bone spicule pigmentation. Many patients with cone-rod degenerations have a defect in the ABCA4 gene with consequent impaired capacity to metabolize vitamin A,^29,30 and, consequently, it has been hypothesized that vitamin A could have an adverse effect on such patients.³¹ No evidence exists that vitamin A will benefit patients with choroideremia or the Bardet-Biedl syndrome.

SOME FUTURE DIRECTIONS

With respect to future directions, some preliminary evidence exists that neuroprotection with ciliary neurotrophic factor (CNTF) will slow the course of retinal degeneration based on studies of animal models of retinitis pigmentosa. The CNTF provides protection by downregulating the photoreceptor cells. A phase 1 study showed that encapsulated cell technology with intravitreal release of CNTF could be well tolerated over 6 months with a few patients reporting improved vision.³² A phase 2/3 study of CNTF is now in progress. Implantation of light-sensitive microchips on or under the retina in patients with advanced RP have been attempted but it is not yet established whether patients achieve useful vision with these devices.^33,34

Retinal transplantation of photoreceptor cells or stem cells under the retina has also been advocated, but it has not been shown that these cells form functional connections with the inner retina.³⁵ Recent phase 1 studies of gene therapy for young adults with a mutation in the RPE65 gene and a severe form of recessive retinitis pigmentosa termed "Leber congenital amaurosis" have used adeno-associated virus-mediated delivery to introduce a human RPE65 gene construct to the RPE.^36-38 The results from 2 trials have suggested modest visual improvement in some adult patients as monitored by psychophysical tests, and studies are in progress to see if greater visual improvement can be achieved safely in younger patients. Whereas gene replacement therapy is an appropriate strategy for recessive mutations, ribozyme-based or RNAi-based therapy, sometimes referred to as gene silencing, is under investigation for dominant mutations.³⁹ Nonviral gene therapy using nanoparticle technology is also under study.⁴⁰ Risk factor analyses of well-defined populations may help to reveal other factors (e.g., diet, environment, modifier genes) that could further slow the course of retinitis pigmentosa with possible implications for treatment.¹¹ RP

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